Prognostic indicators of disease progression in Duchenne muscular dystrophy: A literature review and evidence synthesis

Background Duchenne muscular dystrophy (DMD) is a rare, severely debilitating, and fatal neuromuscular disease characterized by progressive muscle degeneration. Like in many orphan diseases, randomized controlled trials are uncommon in DMD, resulting in the need to indirectly compare treatment effects, for example by pooling individual patient-level data from multiple sources. However, to derive reliable estimates, it is necessary to ensure that the samples considered are comparable with respect to factors significantly affecting the clinical progression of the disease. To help inform such analyses, the objective of this study was to review and synthesise published evidence of prognostic indicators of disease progression in DMD. We searched MEDLINE (via Ovid), Embase (via Ovid) and the Cochrane Library (via Wiley) for records published from inception up until April 23 2021, reporting evidence of prognostic indicators of disease progression in DMD. Risk of bias was established with the grading system of the Centre for Evidence-Based Medicine (CEBM). Results Our search included 135 studies involving 25,610 patients from 18 countries across six continents (Africa, Asia, Australia, Europe, North America and South America). We identified a total of 23 prognostic indicators of disease progression in DMD, namely age at diagnosis, age at onset of symptoms, ataluren treatment, ATL1102, BMI, cardiac medication, DMD genetic modifiers, DMD mutation type, drisapersen, edasalonexent, eteplirsen, glucocorticoid exposure, height, idebenone, lower limb surgery, orthoses, oxandrolone, spinal surgery, TAS-205, vamorolone, vitlolarsen, ventilation support, and weight. Of these, cardiac medication, DMD genetic modifiers, DMD mutation type, and glucocorticoid exposure were designated core prognostic indicators, each supported by a high level of evidence and significantly affecting a wide range of clinical outcomes. Conclusion This study provides a current summary of prognostic indicators of disease progression in DMD, which will help inform the design of comparative analyses and future data collection initiatives in this patient population.


Introduction
Duchenne muscular dystrophy (DMD) is a rare, neuromuscular disease characterised by progressive muscle degeneration caused by mutations in the X-linked DMD gene [1,2]. The DMD gene encodes dystrophin, a structural protein which forms part of complexes predominantly found in muscle cells where it plays a significant role in the stabilisation of cell membranes [3]. To date, over 1,100 mutations have been identified, including 891 responsible for DMD phenotypes [4]. The incidence of DMD has been estimated at between 1 in 3,500 and 5,000 live male births [5,6].
Patients with DMD are diagnosed around the age of four years, but many boys show symptoms earlier due to proximal muscle weakness resulting in delayed physical milestones (e.g., walking, running, and climbing stairs). As the disease progresses, patients become non-ambulatory usually in their early teens, followed by increasing loss of upper limb strength and function [7][8][9][10][11]. Respiratory and cardiac decline ensue, with patients eventually requiring mechanical ventilation support for survival [9,10]. The median life expectancy at birth is around 30 years [12]. At present, there is no cure for DMD, and standard of care is mainly aimed at managing disease symptoms and promoting patient quality of life [13].
In medical research, it is occasionally necessary to pool patient-level data from different studies to indirectly assess the efficacy of a treatment due to low statistical power because of small patient samples and/or the absence of direct comparators in randomised controlled trials (RCTs). To minimize bias in such analyses, it is important to ensure that the populations to be compared are sufficiently homogeneous with respect to factors that would be expected to directly or indirectly affect outcomes of interest [14]. For example, in the context of DMD, it would be relevant to adjust any indirect comparison for the current age of the patient, among other factors, given the progressive, age-related nature of the disease. However, to date, no study has systematically reviewed the body of evidence for factors affecting disease progression outcomes in DMD. To bridge this evidence gap, the objective of this study was to review and synthesise the published evidence on prognostic indicators of disease progression in DMD.

Methods
This literature review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [15]. The study protocol is not publicly available due to intellectual property restrictions.

Selection criteria
Eligibility criteria based on the Population, Intervention, Comparison, Outcomes and Study design (PICOS) framework for study inclusion are presented in Table 1. Only English language texts were included. For the purposes of this review, a prognostic indicator was defined as any factor, either endogenous or exogenous, affecting the clinical progression of disease.

Screening and data extraction
One investigator (NF) initially screened article titles and abstracts for eligibility, and subsequently reviewed full-text versions of selected records. The reason for exclusion was recorded and confirmed by a second investigator (JS). For all articles that met the inclusion criteria upon full-text review, the following information was extracted into a pre-designed data extraction form: Author, year, geographical setting, study design, interventions, patient sample population characteristics, disease progression outcome measures, prognostic indicators, and the impact of the prognostic indicators on disease progression. For the purpose of this review, we only considered statistically significant prognostic indicators (as reported in the included studies).
We synthesised extracted evidence of the impact of identified prognostic indicators of disease progression in DMD into eight outcome categories: cardiac health and function, loss of independent ambulation, lower extremity and motor function, muscle strength, respiratory health and function, scoliosis, survival, and upper extremity function. Although loss of ambulation is a clinical milestone within the lower extremity and motor function domain, we decided to report evidence separately for this factor given its central role in DMD research (e.g., as a primary endpoint in RCTs). Due to the monotonic progression of DMD, we did not

Level of evidence
The level of evidence of included studies was established using a modified version of the grading system of the Centre for Evidence-Based Medicine (CEBM) [16]. Specifically, five levels of evidence were designated based on study design: (1) systematic review of randomised trials or n-of-1 trials, (2) randomised trial or observational study with dramatic effect, (3) non-randomised controlled cohort/follow-up study, (4) case-series, case-control studies, or historically controlled studies, and (5) mechanism-based reasoning. For reporting purposes, we categorised evidence levels 1 and 2 as "high level of evidence", level 3 as "moderate level of evidence", and levels 4 and 5 as "low level of evidence".

Results
The search was performed on April 26 2021, and resulted in the identification of 3,018 publications (including journal articles and congress/conference abstracts) reporting evidence of prognostic indicators of disease progression in DMD (Fig 1). Of these, 740 records were duplicates, 1,966 excluded following title and abstract screening, and 312 selected for full-text review. An additional 54 articles were included from the reference searches of identified systematic literature reviews (SLRs) and meta-analyses (MAs). Finally, 294 publications were considered for data extraction, with 135 studies reporting statistically significant prognostic indicators of disease progression that were subsequently included for evidence synthesis and grading. Summary details of the included studies are presented in Table 2. Identified studies encompassed 25,610 patients with DMD from 18 countries (Argentina, Australia, Belgium, Canada, China, Denmark, Egypt, France, Germany, Holland, India, Italy, Japan, Korea, Sweden, Turkey, the United Kingdom and the United States). We identified a total of 23 prognostic indicators of disease progression in DMD. Endogenous indicators included age at diagnosis, age at onset of symptoms, DMD genetic modifiers, DMD mutation type, height, weight and body mass index (BMI). Exogenous indicators included ataluren treatment, ATL1102, cardiac medication, drisapersen, edasalonexent, eteplirsen, glucocorticoid exposure (including age at glucocorticoid treatment initiation, dose, duration of exposure, pharmacological agent, and regimen), idebenone, lower limb surgery, orthoses, oxandrolone, spinal surgery, TAS-205, vamorolone, vitlolarsen, and ventilation support. The evidence for these prognostic indicators across the pre-defined outcome categories is summarised below and illustrated in Fig 2.

Cardiac health and function
We identified 29 studies presenting evidence of prognostic indicators of disease progression in DMD measured in terms of cardiac health and function [17-45, 91, 111, 199]. In total, seven prognostic indicators were identified: BMI, cardiac medication, DMD genetic modifiers, DMD mutation type, glucocorticoid exposure, idebenone and ventilation support ( Table 2). Angiotensin-converting enzyme (ACE) inhibitors, including timing of treatment initiation, have been shown to be significantly associated with improved left ventricular ejection fraction (LVEF) [

Survival
We identified 13 studies presenting evidence of prognostic indicators of disease progression in DMD measured in terms of survival [25, 42, 43, 49, 51-60]. In total, five prognostic indicators were identified: cardiac medication, glucocorticoid exposure, left ventricular assist devices, spinal surgery, and ventilation support (

Upper extremity function
We identified 5 studies presenting evidence of prognostic indicators of disease progression in DMD measured in terms of upper extremity function [51,92,93,96,140]. In total, two prognostic indicators were identified: glucocorticoid exposure (including pharmacological agent) and ATL1102 treatment (

Discussion
In many disease areas, including DMD, RCTs are commonly unavailable, resulting in the need to indirectly compare treatment effects, for example, by pooling individual patient-level data from multiple sources. However, to derive reliable estimates, it is necessary to ensure that the samples considered are comparable with respect to factors significantly affecting the clinical progression of the disease. To help inform such analyses, the objective of this study was to review and synthesise the published evidence of prognostic indicators of disease progression in DMD. From our literature search, we identified 23 factors significantly affecting disease progression outcomes in DMD, namely age at diagnosis, age at onset of symptoms, ataluren treatment, ATL1102, BMI, cardiac medication, DMD genetic modifiers, DMD mutation type, drisapersen, edasalonexent, eteplirsen, glucocorticoid exposure, height, idebenone, lower limb surgery, orthoses, oxandrolone, spinal surgery, TAS-205, vamorolone, vitlolarsen, ventilation support, and weight. Of these, two endogenous and two exogenous core prognostic indicators were designated, each supported by a high level of clinical evidence. The most commonly examined prognostic indicator identified in the literature related to treatment with glucocorticoids-the cornerstone of the current pharmacological management of DMD. This core exogenous factor was found to significantly impact a wide range of disease progression outcomes, including loss of independent ambulation, lower extremity and motor function, muscle strength, respiratory health and function, survival, and upper extremity function (high level of evidence); cardiac health and function (moderate level of evidence); and possibly risk of developing scoliosis (low level of evidence). The body of evidence, spanning a total of 73 individual studies, encompassed various commonly reported features of glucocorticoid therapy, such as age at treatment initiation, dose, duration of exposure, pharmacological agent, and regimen.
The second exogenous core prognostic indicator of disease progression in DMD was cardiac medication, supported by data from a total of 13 studies of varying levels of evidence ( Fig  2). As expected, this indicator only concerned cardiac health and function (with the exception of a single study of low evidence level showing an impact on survival). Even so, bearing in mind that cardiomyopathy has emerged as one of the leading causes of death in the aging DMD population in the presence of the routine use of mechanical ventilation support [12], the significance of this indicator should not be underestimated, in particular when comparing samples encompassing patients residing in more advanced stages of the disease.
The two endogenous core prognostic indicators of disease progression in DMD identified in our review were DMD genetic modifiers and DMD mutation type. Although more research is needed to quantify the impact of specific modifiers and mutations, emerging data show that these genetic aspects may play a non-trivial role in the overall progression of the disease. These findings underscore the importance of collecting genetic data from DMD patients as part of studies and patient registries.
Our study is subject to three specific limitations. First, our review did not cover grey literature, which means that evidence for some indicators of disease progression in DMD might have not been fully identified. However, given the comprehensive scope of our search and the limited body of clinical evidence disseminated in non-indexed journals, the impact of this limitation is expected to be negligible (in particular in terms of detecting novel prognostic indicators currently not included in our synthesis). Second, for interpretation of results, it is important to keep in mind that our study did not seek to assess the efficacy or effectiveness of current disease interventions, nor the sensitivity of specific indicators, but rather identify factors that have been shown to significantly alter the clinical progression of DMD (irrespective of magnitude). Although we only considered statistically significant factors, this means that it is not possible to discern the relative clinical importance, or relevance, of included indicators. Finally, the fact that we only reported statistically significant and not also non-significant results means that we were more likely to accept false positive than false negative conclusions of specific indicators. That being said, collating and synthesizing also non-significant results, of which a non-trivial proportion (β) would be expected to be false, were outside the scope of this review.
In conclusion, we identified a total of 23 prognostic indicators of disease progression in DMD, of which cardiac medication, DMD genetic modifiers, DMD mutation type, and glucocorticoid exposure were designated core indicators significantly affecting a wide range of clinical outcomes. Our up-to-date summary of prognostic indicators in DMD should be helpful to inform the design of comparative analyses and future data collection initiatives in this patient population.